Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes

Satoru Kariya, Sadao Isozaki, Katsuyoshi Uchino, Tokuji Suzuki, Shizuo Narimatsu

Research output: Contribution to journalArticle

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Abstract

The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3- phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4- fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F- 2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 μM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with K(m) values of 2 to 4 μM had intrinsic clearance values (V(max)/K(m)) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a K(m) value of 17 μM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.

Original languageEnglish
Pages (from-to)1511-1514
Number of pages4
JournalBiological and Pharmaceutical Bulletin
Volume19
Issue number11
Publication statusPublished - Nov 1996
Externally publishedYes

Fingerprint

Cinnarizine
Flunarizine
Microsomes
Cytochrome P-450 Enzyme System
Cell Line
Cytochrome P-450 CYP2D6
Hydroxylation
Cytochromes c2
Cytochrome P-450 CYP1A1
Cytochrome P-450 CYP2B6
Pharmaceutical Preparations

Keywords

  • cinnarizine
  • CYP2B6
  • CYP2D6
  • flunarizine
  • human cytochrome P450
  • p- hydroxylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. / Kariya, Satoru; Isozaki, Sadao; Uchino, Katsuyoshi; Suzuki, Tokuji; Narimatsu, Shizuo.

In: Biological and Pharmaceutical Bulletin, Vol. 19, No. 11, 11.1996, p. 1511-1514.

Research output: Contribution to journalArticle

Kariya, Satoru ; Isozaki, Sadao ; Uchino, Katsuyoshi ; Suzuki, Tokuji ; Narimatsu, Shizuo. / Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. In: Biological and Pharmaceutical Bulletin. 1996 ; Vol. 19, No. 11. pp. 1511-1514.
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abstract = "The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3- phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4- fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F- 2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 μM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with K(m) values of 2 to 4 μM had intrinsic clearance values (V(max)/K(m)) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a K(m) value of 17 μM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.",
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T1 - Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes

AU - Kariya, Satoru

AU - Isozaki, Sadao

AU - Uchino, Katsuyoshi

AU - Suzuki, Tokuji

AU - Narimatsu, Shizuo

PY - 1996/11

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N2 - The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3- phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4- fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F- 2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 μM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with K(m) values of 2 to 4 μM had intrinsic clearance values (V(max)/K(m)) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a K(m) value of 17 μM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.

AB - The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3- phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4- fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F- 2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 μM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with K(m) values of 2 to 4 μM had intrinsic clearance values (V(max)/K(m)) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a K(m) value of 17 μM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.

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